Obesity which has become common in the US and among the VA population is a major cause of hypertension, a principal reversible risk factor for cardiovascular disease. However, the mechanisms underlying the relationship between obesity and hypertension remain largely unknown. The goal of this proposal is to identify the neuronal and molecular processes that control sympathetic activity and blood pressure and how dysregulation in these processes contribute to obesity-associated cardiovascular risks. This proposal is based on the hypothesis that mTORC1 signaling in the hypothalamic arcuate nucleus neurons are critical for sympathetic and blood pressure regulation with important pathophysiological implications in obesity. We will use a multidisciplinary strategy combining unique genetically engineered mouse models that permit selective modulation of key pathways in defined neurons with novel and cutting edge neuro-technologies to precisely and remotely modulate the firing of distinct arcuate nucleus neuronal populations in freely moving animals with sophisticated integrative physiology for sympathetic and cardiovascular phenotyping. We will investigate the contribution of mTORC1 signaling in arcuate nucleus neurons that express proopiomelanocortin (POMC) or agouti-related protein (AgRP) to the regulation of sympathetic activity and arterial pressure and obesity- associated hypertension and sympathetic nerve activation. We will also use chemogenetic and optogenetics to probe the functional relevance of arcuate nucleus POMC and AgRP neurons for the regulation of arterial pressure and sympathetic activity in normal and obese states. This work should unravel novel mechanisms that underlie obesity-associated sympathetic activation and hypertension, making our work of high clinical relevance. Insights into the cellular and molecular processes that control the sympathetic tone that regulates cardiovascular function may make it possible to selectively interfere with the damage obesity inflicts on cardiovascular sympathetic functions.